The proposed research is designed to evaluate the molecular basis for the antiproliferative action of agents which interfere with the metabolism and/or function of polyamines. Though the latter are known to be elevated, and presumably involved, in cell proliferation their critical significance in this process is unknown. Methylglyoxal-bis(guanylhydrazone) (MGBG), an agent used in the treatment of human leukemia, will be taken as the primary experimental tool but other drugs having similar actions will also be used. MGBG effectively inhibits cell proliferation, acts as a potent inhibitor of spermidine biosynthesis and has recently been found to alter the ultrastructure, function and replication of mitochondria in proliferating normal or tumor cell populations. Possible interrelationships between each of these three main drug actions will be sought. Analogs of MGBG and recently identified inhibitors of putrescine and spermidine metabolism such as alpha-difluoro methyl-ornithine will also be studied. The objectives of this study are (a) to determine the relevance of proliferation (b) to elucidate the molecular basis for MGBG-induced mitochondrial damage with particular attention to possible polyamine involvement (c) to examine the relevence of mitochondrial damage to inhibition of cell proliferaton (d) to elucidate the cellular function of polyamines (e) to assess their potential as a target for cancer chemotherapy (f) to investigate the possible involvement of polyamines in in vitro chemical carcinogenesis. Most of the basic in vitro work will be performed with murine leukemia L1210 cells. Among the parameters that will be examined in assessing drug effects are cell growth and cytotoxicity by routine cell counting and culturing techniques, ultrastructural changes by electron microscopy, polyamine and nucleotide pool size analyses by high pressure liquid chromatography, integrity and synthesis of mitohondrial and nuclear DNA by precursor incorporation and integrity of nuclear- and mitochondrial-coded cytochromes by spectral analysis.